The present invention relates to novel heterocyclic compounds and pharmaceutically-acceptable salts thereof, processes for their production and formulation and use as pharmaceuticals.
2-Thienylbenzoxazoles with anti-aggregating activity are described in Eur. J. Med. Chem. (1994) 29:75.
EP-A-0116938 and J. Med. Chem. (1987) 30 62 describe heteroaryloxycarboxamides as lipolysis inhibitors useful in the treatment of ischemic heart disease and hypertriglyceridemia.
WO-A-9406783 and WO-A-9406782 describe heteroarylsulphonamides having insecticidal, nematicidal, acaricidal and fungicidal activity.
WO-A-9604251 describes aryloxy derivatives of heteroaryl compounds as bradykinin inhibitors.
Heteroaryl compounds are described as fibrinogen antagonists in WO-A-9408962.
EP-A-0498722 describes amide derivatives of heteroaryl compounds.
Quinoxalines are disclosed as performance enhancers for animals in EP-A-0456067.
Benzimidazoles are described as dopamine antagonists in WO-A-9422839.
DE-A-4237617 discloses imidazoles as antiparasitic agents.
Phosphodiesterases (PDE) and Tumour Necrosis Factor (TNF), their modes of action and the therapeutic utilities of inhibitors thereof, are described in WO-A-9720833 and PCT/GB97/01361, the contents of which are incorporated herein by reference. The same documents disclose carboxamides having utility as PDE and TNF inhibitors.
This invention is directed to the pharmaceutical use of a compound of formula (i) below to treat disease states, for example disease states associated with proteins which mediate cellular activity, for example by inhibiting tumour necrosis factor and/or by inhibiting phosphodiesterase IV. According to the invention, novel compounds are of formula (i): 
wherein (1) X is N and (a) Z is xe2x95x90CR1xe2x80x94CR2xe2x95x90 and Y is N, (b) Z is xe2x95x90CR1xe2x80x94 and Y is O, S or NR4, or (c) Z is xe2x95x90CR1xe2x80x94Nxe2x95x90 and Y is CR2, or (2) X is NR4, Z is xe2x80x94CR1xe2x95x90 and Y is N;
Q is O or S;
R1 and R2 are the same or different and are each COR6, C(xe2x95x90NOR6)R13, alkyl-C(xe2x95x90NOR6)R13, NR8R9, CON(R6)2, halogen, CF3, CN, CO2H, CO2R10, R6, CO-het where het is a heterocyclic ring (such as morpholine or piperidine) attached via a N atom in the ring and optionally substituted with one or more R14, or 
R3 is OH, thioalkyl, or C1-4 alkoxy or cycloalkoxy each optionally substituted with one or more halogens,
R4 is H or alkyl;
R5 is aryl or heteroaryl, either of which may be optionally substituted with one or more substitutents chosen from halogen, optionally halogen-substituted alkyl, hydroxy, optionally halogen-substituted alkoxy, CO2H, CO2R10, CONR11R12, COR10, SO2R10, SO2NR11R12, NR8R9 and CN;
each R6 is independently H or a group selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkl, heteroarylalkyl and heterocycloalkyl, any of which groups is optionally substituted at any position with R7;
R7 is alkyl, hydroxy, OR10, NR8R9, CN, CO2H, CO2R10, CONR11R12 or COR10,
R8 is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkly, heterocycloalkyl, alkylcarbonyl, alkoxycarbonyl, arylcarbonyl, heteroarylcarbonyl, heterocyclocarbonyl, alkylsulphonyl, arylsulphonyl, heteroarylsulphonyl or heterocyclosulphonyl, R, is H, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclo, aralkyl, heteroarylalkyl or heterocycloalkyl; or NR8R9 is a heterocyclic ring (such as morpholine or piperidine) optionally substituted with R14;
R10 is alkyl cycloalkyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl or heterocycloalkyl;
R13 and R12 are the same or different and are each H or R10;
R13 is R10 optionally substituted with one or more R7;
R14 is alkyl, arylalkyl or heteroarylalkyl; and
R15 is alkyl, V is O or S, and n is 2-4; and pharmaceutically-acceptable salts thereof.
Compounds of the invention have a bicyclic aryl nucleus. Depending on the definitions of X, Y, and Z, they are (1a) quinoxalines, (1b) benzoxazole; benzthiazoles or benzimidazoles, (1c) quinazolines or (2) benzimidazoles (differently substituted from those under 1b). Preferred compounds are defined in the subclaims.
Suitable pharmaceutically-acceptable salts are pharmaceutically-acceptable base salts and pharmaceutically-acceptable acid addition salts. Certain of the compounds of formula (i) which contain an acidic group form base salts. Suitable pharmaceutically-acceptable base salts include metal salts, such as alkali metal salts for example sodium salts, or organic amine salts such as that provided with ethylenediamine.
Certain of the compounds of formula (i) which contain an amino group from acid addition salts. Suitable acid addition salts include pharmaceutically-acceptable inorganic salts such as the sulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide and pharmaceutically-acceptable organic acid addition salts such as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, methane-sulphate, xcex1-ketoglutarate, xcex1glycerophosphate and glucose-1-phosphate. The pharmaceutically-acceptable salts of the compounds of formula (i) are prepared using conventional procedures.
It will be appreciated by those skilled in the art that some of the compounds of formula (i) may exist in more than one tautomeric form. This invention extends to all tautomeric forms. It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centers in a compound of formula (i) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers, and diastereoisomers and mixtures including racemic mixtures thereof.
When used herein the term alkyl whether used alone or when used as a part of another group includes straight and branched chain alkyl groups containing up to 6 atoms. Alkoxy means an alkyl-O-group in which the alkyl group is as previously described. Cycloalkyl includes a non-aromatic cyclic or multicyclic ring system of about 3 to 10 carbon atoms. The cyclic alkyl may optionally be partially unsaturated. Cycloalkoxy means a cycloalkyl-I-group in which cycloalkyl is as defined above. Aryl indicates an aromatic monocyclic or multicyclic carbocyclic group containing about 6 to 10 carbon atoms. Arylalkyl means an aryl-alkyl-group wherein the aryl and alkyl are as described herein. Heteroarylalkyl means a heteroaryl-alkyl group and heterocycloalkyl means a heterocyclo-alkyl group. Alkylcarbonyl means an alkyl-CO-group in which the alkyl group is as previously described. Arylcarbonyl means an aryl-CO-group in which the aryl group is as previously described. Heteroarylcarbonyl means a heteroaryl-CO-group and heterocyclocarbonyl means a heterocyclo-CO-group. Arylsulphonyl means an aryl-SO2-group in which the aryl group is as previously described. Heteroarylsulphonyl means a heteroaryl-SO2-group and heterocyclosulphonyl means a heterocyclo-SO2-group. Alkoxycarbonyl means an alkyloxy-CO-group in which the alkoxy group is as previously described. Alkylsulphonyl means an alkyl-SO2-group in which the alkyl group is as previously described. Heterocyclic ring means about a 5 to about a 10 membered monocyclic or multicyclic ring system (which may saturated or partially unsaturated) wherein one or more of the atoms in the ring system is an element other than carbon chosen from amongst nitrogen, oxygen or sulphur atoms. Heteroaryl means about a 5 to about a 10 membered aromatic monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur, if desired, a N atom may be in the form of an N-oxide. Heterocyclo means about a 5 to about a 10 membered saturated or partially saturated monocyclic or multicyclic hydrocarbon ring system in which one or more of the atoms in the ring system is an element other than carbon, chosen from amongst nitrogen, oxygen or sulphur. Halogen means fluorine, chlorine, bromine or iodine.
xe2x80x9cTNF mediated disease or disease statesxe2x80x9d means any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another cytokine to be released, such as but not limited to IL-1 or IL-6. A disease state in which IL-1, for instance, is a major component, and whose production or action is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF. As TNF-xcex2 (also known as lymphotoxin) has close structural homology with TNF-xcex1 (also known as cachectin), and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-xcex1 and TNF-xcex2 are inhibited by the compounds of the present invention and thus are herein referred to collectively as xe2x80x9cTNFxe2x80x9d unless specifically delineated otherwise.
This invention relates to a method for mediating or inhibiting the enzymatic activity or catalytic activity of PDE IV in a mammal in need thereof and for inhibiting the production of TNF in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
PDE IV inhibitors are useful in the treatment of a variety of allergic and inflammatory diseases, including asthma, chronic bronchitis, chronic obstructive airways disease, chronic pulmonary inflammatory disease, atopic dermatitis, atopic eczema, urticaria, allergic rhinitis, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, eosinophilic granuloma, psoriasis, Bechet""s disease, erythematosis, anaphylactoid purpura nephritis, joint inflammation, arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis and osteoarthritis, septic shock, ulcerative coritis Crohn""s disease, reperfusion injury of the myocardium and brain, chronic glomerulonephritis, endotoxic shock and adult respiratory distress syndrome. In addition, PDE IV inhibitors are useful in the treatment of diabetes insipidus and conditions associated with cerebral metabolic inhibition, such as cerebral senility, senile dementia (Alzheimer""s disease), memory impairment associated with Parkinson""s disease, depression and multi-infarct dementia. PDE IV inhibitors are also useful in conditions ameliorated by neuroprotectant activity, such as cardiac arrest, stroke and intermittent claudication. Additionally, PDE TV inhibitors could have utility as gastroprotectants. A preferred embodiment of the therapeutic methods of the present invention is the treatment of asthma.
The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibitions such as by decreased replication, directly or indirectly, by the TNF inhibitors of Formula (i). Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpes group of viruses, such as, but not limited to, Herpes zoster and Herpes simplex. 
This invention more specifically relates to a method of treating a mammal, afflicted with a human immunodeficiency virus (HIV), which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (i) or a pharmaceutically-acceptable salt thereof.
The compounds of this invention may be also be used in association with the veterinary treatment or animals, other than humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to feline immunodeficiency virus (FIV) or other retroviral infection such as equine infectious anaemia virus, caprine arthritis virus, visna virus, maedi virus and other lentiviruses.
The compounds of this invention are also useful in treating parasites, yeast and fungal infections, where such yeast and fungi are sensitive to upregulation by TNF or will elicit TNF production in vivo. A preferred disease state for treatment is fungal meningitis.
The compounds of formula (i) preferably in pharmaceutically-acceptable form. By pharmaceutically-acceptable form is meant, inter alia, of a pharmaceutically-acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. A pharmaceutically-acceptable level of purity will generally be at least 50% excluding normal pharmaceutical additives, preferably 75%, more preferably 90% and still more preferably 95%.
The invention further provides a process for the preparation of a compound of formula (i), in which R1-R15 and Q, X, Y and Z are as defined above. It will be appreciated that functional groups such as amino, hydroxyl or carboxyl groups present in the various compounds described below, and which it is desired to retain, may need to be in protected forms before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details, see Protective Groups in Organic Synthesis, Wiley Interscience, T W Greene. Thus a process for preparing compounds of formula (i) in which R1 contains an xe2x80x94OH comprises deprotecting (for example by hydrogenolysis or hydrolysis) a compound of formula (i) in which R3 contains an appropriate xe2x80x94OP wherein P represents a suitable protecting group (eg benzyl).
A process for the preparation of a compound of formula (i) comprises reaction of an appropriate carboxylic acid of formula (ii) with a suitable amine of formula (iii) 
wherein R3a represents R3 as defined in relation to formula (i) or a group convertable to R3 and R4a and R5a, similarly represent R4 and R5 or groups convertable to R4 and R5 respectively and Xxe2x80x2, Yxe2x80x2 and Zxe2x80x2 represent X, Y and Z or groups convertable to X, Y and Z respectively; and thereafter, if required, converting any group R3a to R3 and/or R4a to R4 and/or R5a to R5 and/or Xxe2x80x2 to X and/or Yxe2x80x2 to Y and/or Zxe2x80x2 to Z. The reaction of a carboxylic acid of formula (ii) with an amine of formula (iii) may be carried out under any suitable conditions known to those skilled in the art. Preferably, the carboxylic acid is converted into an acid chloride, mixed anhydride or other activated intermediate prior to reaction with an amine of formula (iii). Preferably, the reaction with the amine of formula (iii) is carried out in the presence of a suitable base, for example an amine base such as triethylamine, preferably in an appropriate solvent such as dichloromethane. In some cases a stronger base, such as sodium hydride, and a polar solvent such as dimethylformamide, will be required.
Carboxylic acids of formula (ii) are either commercially available, previously described compounds or are prepared using standard conditions known to those skilled in the art. For example, a carboxylic acid of formula (ii) is conveniently prepared from a compound of formula (iv), either by formylation to provide an aldehyde of formula (v) followed by oxidation to provide the acid of formula (ii), or by bromination to provide bromide of formula (vi) followed by carboxylation to provide an acid of formula (ii). 
Formylation of a compound of formula (iv) may be carried out under standard conditions known to those skilled in the arts for example by using phosphorous oxychloride and dimethylformamide at elevated temperature. Oxidation of an aldehyde of formula (v) may be carried out using appropriate conditions known to those skilled in the art, for example by using sodium chlorite and sodium phosphate in water/t-butanol in the presence of an acid scavenger such as 2-methyl-2-butene. Bromination of a compound of formula (iv) can be carried out using standard conditions, for example by using bromine in an appropriate solvent such as methanol. Carboxylation of a bromide of formula (vi) can conviently be achieved by the use of an organometal catalyst, such as a palladium catalyst in the presence of an appropriate base in a suitable solvent.
A compound of formula (iv) may be commercially available, a previously described compound or may be prepared using standard conditions known to those skilled in the art. For example, procedures are described in EP-A-0701907, EP-A-0116938, DE-A-4237417, J. Med. Chem. (1987) 30 62, J. Chem. Soc. Perkin Trans. I (1982) 357 and J. Chem. Soc. Perkin Trans. I (1949) 3012, J. Chem. Soc. (1928) 2393 and J. Chem. Soc. (1964) 4645.
Amines of formula (iii) are either commercially available, previously described compounds or are prepared using standard conditions known to those skilled in the art.
A compound of formula (i) may also be prepared by interconversion of other compounds of formula (i). For example, a compound in which R1 contains an alcohol function maybe prepared by reduction of a compound of formula (i) in which R1 contains a carbonyl function.
By way of further example, compounds in which R1 and/or R2contains an oxime may be prepared from compounds in which R1 and/or R2 contain a carbonyl group. This transformation may be carried out using any appropriate standard conditions known to those skilled in the art. Compounds of formula (i) in which R1 and/or R2 contain a carbonyl group may be reduced using standard conditions known to those skilled in the art (for example with sodium borohydride in an appropriate solvent) to provide compounds in which R1 and/or R2 contains an alcohol group. Compounds in which R1 and/or R2 is alkyl may be prepared by reduction of compounds in which R1 and/or R2 is CO-alkyl using standard conditions known to those skilled in the art (for example hydrazine hydrate in the presence of a suitable base in an appropriate solvent). Other transformations may be carried out on compounds of formula (i) in which R1 and/or R2 contains a carbonyl group. Such transformations include, but are not limited to, reductive amination and alkylation. Any of the above transformations may be carried out either at the end of the synthesis or on an appropriate intermediate. Compounds of formula (i) in which Z is CS may be prepared from compounds of formula (i) in which Z is CO using any appropriate conditions known to those skilled in the art, for example by using Lawesson""s reagent.
It will be appreciated that where a particular stereoisomer of formula (i) is required, this may be obtained by conventional resolution techniques such as high performance liquid chromatography or the synthetic processes herein described may by performed using the appropriate homochiral starting material.
A compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may be administered per se or, preferably, as a pharmaceutical composition also comprising a pharmaceutically-acceptable carrier.
Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (i) or where appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, and a pharmaceutically-acceptable carrier.
The active compound may be formulated for administration by any suitable route, the preferred route depending upon the disorder for which treatment is required, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage. Advantageously, the composition is suitable for oral, rectal, topical, parenteral administration or through the respiratory tract. Preparations may be designed to give slow release of the active ingredient.
The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion tecniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc, the compounds of the invention are effective in the treatment of humans.
The compositions of the invention may be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, suppositories, reconstitutable powders, or liquid preparations such as oral or sterile parenteral solutions or suspensions. Topical formulations are also envisaged where appropriate.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example microcrystalline cellulose, lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically-acceptable wetting agents such as sodium lauryl sulphate.
The solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
Such operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
Oral liquid preparations may be in the form of, for example, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia, non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring or colouring agents.
Compositions may also suitably be presented for administration to the respiratory tract as a snuff or an aerosol or solution for a nebuliser, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case the particles of active compound suitably have diameters of less than 50 microns, such as from 0.1 to 50 microns, preferably less than 10 microns, for example from 1 to 10 microns, 1 to 5 microns or from 2 to 5 microns. Where appropriate, small amounts of other anti-asthmatics and bronchodilators for example sympathomimetic amines such as isoprenaline, isoetharine, salbutamol, phenylephrine and ephedrine; corticosteroids such as prednisolone and adrenal stimulants such as ACTH may be included.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
Advantageously, adjuvants such as local anaesthetic, a preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% to 99% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
Compounds of formula (i), or if appropriate a pharmaceutically-acceptable salt thereof and/or a pharmaceutically-acceptable solvate thereof, may also be administered as a topical formulation in combination with conventional topical excipients.
Topical formulations may be presented as, for instance, ointments, creams or lotions, impregnated dressings, gels, gel sticks, spray and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The formulations may contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
Suitable cream, lotion, gel, stick, ointment, spray or aerosol formulations that may be used for compounds of formula (i) or if appropriate a pharmaceutically-acceptable salt thereof are conventional formulations well known in the art, for example, as described in standard text books such as Harry""s Cosmeticology published by Leonard Hill Books, Remington""s Pharmaceutical Sciences, and the British and U.S. Pharmacopoeias.
Suitably, the compound of formula (i), or if appropriate a pharmaceutically-acceptable salt thereof will comprise from about 0.5 to 20% by weight of the formulation, favourably from about 1 to 10%, for example 2 to 5%.
The dose of the compound used in the treatment of the invention will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and the relative efficacy of the compound. However, as a general guide suitable unit doses may be 0.1 to 1000 mg, such as 0.5 to 200, 0.5 to 100 or 0.5 to 10 mg, for example 0.5, 1, 2, 3, 4 or 5 mg; and such unit doses may be administered more than once a day, for example 2, 3, 4, 5 or 6 times a day, but preferably 1 or 2 times per day, so that the total daily dosage for a 70 kg adult is in the range of about 0.1 to 1000 mg, that is in the range of about 0.001 to 20 mg/kg/day, such as 0.007 to 3, 0.007 to 1.4, 0.007 to 0.14 or 0.01 to 0.5 mg/kg/day, for example 0.01, 0.02, 0.04, 0.05, 0.06, 0.08, 0.1 or 0.2 mg/kg/day, and such therapy may extend for a number of weeks or months.
When used herein the term xe2x80x9cpharmaceutically-acceptablexe2x80x9d encompasses materials suitable for both human and veterinary use.